1. Field of the Invention
The present invention relates to medicinally useful novel amidino derivatives, to their pharmacologically acceptable salts or solvates, and to blood clotting factor VIIa inhibitors, anticoagulants and thrombosis therapeutic agents containing them as active ingredients.
2. Related Background Art
Destruction of blood vessels in the body triggers rapid production of thrombin to prevent death by bleeding. On the other hand, overproduction of thrombin accompanying inflammation reaction at damaged blood vessels leads to thrombosis, which impairs the functioning of important organs. Thrombin inhibitors such as heparin and warfarin, which inhibit thrombin production or directly inhibit thrombin activity, have long been used as anticoagulants for treatment or prevention of thrombosis. However, because such drugs have not been very satisfying from a therapeutic standpoint, research and development have been pursued on a worldwide scale for new anticoagulants with excellent dose response, low risk of hemorrhage and suitability for oral administration.
Incidentally, mechanisms of blood clotting had been divided into two types, of the “intrinsic coagulation pathway” which is initiated by activation of Factor XII (FXII) by contact with negatively charged substances, or of the “extrinsic coagulation pathway” which is activated by Tissue Factor (TF) and Factor VII (FVII). It is extrinsic coagulation that is implicated in thrombosis because of specific expression of TF observed in the clinical condition. In the blood clotting cascade, compounds that inhibit blood clotting factor VIIa, which is furthest upstream in the extrinsic coagulation pathway, are believed to be useful as prophylactic and/or therapeutic agents for clinical conditions involving thrombogenesis in which extrinsic clotting mechanisms are implicated. In addition, blood clotting factor VIIa inhibitors, unlike thrombin inhibitors, are expected to produce milder hemorrhage since the intrinsic coagulation pathway still remains, and are thus believed to be useful from this viewpoint as well.
Such compounds that have been conventionally known to inhibit blood clotting factor VIIa include amidinonaphthol derivatives, (Tetrahedron, Vol. 55, p. 6219, 1999), amidino derivatives (International Publication No. WO99/41231), N-sulfonyl dipeptide derivatives (International Publication No. WO00/58346), 6-[[(allyl)oxy]methyl]naphthalene-2-carboximidamide derivatives (International Publication No. WO00/66545), and the like.
However, none of the publicly known compounds of the prior art have given satisfactory results in terms of inhibiting activity against blood clotting factor VIIa.